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Zeroing In On Dark Matter

If the human genome – the complete set of DNA blueprints in a cell for building a human being — is truly “the book of life, ” as it has been called, then 99 percent of life’s book is gobbledygook.

Only 1 percent of the DNA contains genetic instructions for making the body’s proteins; most of the rest of it has no known purpose, earning it the unappealing title of “junk DNA” or the more ominous sounding “dark matter.” In addition to containing all of life’s necessary genetic instructions, the 1 percent had also been home to all known cancer-causing mutations.

Until recently.

Levi Garraway, MD, PhD

When scientists from Dana-Farber and the Broad Institute began searching the “dark matter” of malignant melanoma cells, they were stunned to discover a pair of DNA mutations that, together, occurred in 71 percent of the melanoma tumors from which the cells came. These newly found mutations are the first to be discovered in the dark matter, and, in fact, they are the most frequently occurring melanoma mutations yet found anywhere, says Levi Garraway, MD, PhD, of Dana-Farber and the Broad and the article’s senior author.

“This new finding represents an initial foray into the ‘dark matter’ of the cancer genome,” notes Garraway, whose report was published in the Jan. 24 issue of Science Express. Franklin Huang, MD, PhD, in Garraway’s lab is co-first author of the report along with Harvard MD-PhD student Eran Hodis, of Dana-Farber and the Broad.

The precise location of the two mutations is not all that surprising: while they occur in the non-coding DNA of the genome, they are right next to a known gene called TERT that is often overexpressed in cancer cells. The newly found mutations affect a segment of DNA known as a promoter, situated next to the TERT gene, which controls the activity of the gene.

“Considered as a whole, these two TERT promoter mutations are even more common than BRAF mutations in melanoma,” Garraway explains. “Altogether, this discovery could cause us to think more creatively about the possible benefits of targeting TERT in cancer treatment or prevention.”

The researchers said these same two mutations are also present in cell lines from some other malignancies, and that preliminary evidence indicates they might be unusually common in bladder and liver cancers.